Our proposed research has the very broad goals of 1) determining the effects of alcohol intake and/or of liver disease resulting from this on the metabolism and intestinal absorption of key vitamins and sedatives, 2) defining optimal dietary therapy for patients with chronic recurrent encephalopathy resulting from alcoholic liver disease, and 3) elucidating cerebral growth and development in offspring of alcohol-consuming pregnant animals (fetal-alcohol syndrome). (a) As regards the effects of alcohol and of alcohol-induced liver disease on vitamin metabolism, we propose to study in depth the effects of each on the synthesis, plasma binding, distribution and degradation of pyridoxal 5'-phosphate (PLP) (the active coenzyme form of vitamin B6). This will be carried out in vivo in man and in various animal models measuring net PLP synthesis from pyridoxine, PLP binding in plasma and PLP decay from plasma. Complementary mechanistic studies are planned with subcellular liver fractions. (b) As regards the metabolism of sedatives in the presence of liver damage, we will assess the pharmacokinetics of chlordiazepoxide (Librium R), lorazepam and paraldehyde. The aim is to determine what effect liver injury has on the disposition of these drugs which are used often in alcoholics with concomitant liver disease and to define the optimal agent. (c) As regards vitamin absorption, we will continue our studies on the mechanisms which govern intestinal thiamine transport. We will investigate the role of Na-K stimulated ATPase, and the effect of alcohol on this, on thiamine absorption, the effect of folate deficiency on thiamine transport via the gut, and the effect of alcohol in man on thiamine absorption. (d) As regards the dietary management of chronic encephalopathy, we propose to extend our promising pilot studies to assess further in a controlled manner the beneficial role of vegetable protein (low in methionine) in the treatment of this disorder. (e) Finally, as regards the fetal-alcohol syndrome studies, we plan to study fetal and neonatal cerebral regional DNA and RNA metabolism in offspring of rats kept on chronic alcohol.